ASH 2012

ATLANTA – It doesn’t get more personal than this: genetic studies of individual patients can predict who is at increased risk for treatment-related toxicity or death, reported investigators at the annual meeting of the American Society of Hematology.

For example, a single nucleotide polymorphism (SNP) in the Wilms tumor gene (WT1) appears to predict lower risk for treatment-related mortality in children of African American and Asian ancestry with acute myeloid leukemia, reported Dr. Phoenix A. Ho from the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

Other recently identified polymorphisms appear to increase the risk of cardiotoxicity from exposure to anthracyclines in chemotherapy regimens, reported Dr. Smita Bhatia from the City of Hope Comprehensive Cancer Center in Duarte, Calif.

Protection from toxicity

Dr. Ho and his colleagues had previously identified mutations in the exon 7 region of WT1, a tumor suppressor and transcription factor gene that is over-expressed in an estimated 81% of AML cells compared with normal hematopoietic cells. Mutations in WT1 found in about 8% of children with AML are associated with worse prognosis, Dr. Ho said.

But during their investigation of mutations, the researchers also found apparently favorable single-nucleotide polymorphisms (SNPs), specifically a normal variant labeled rs16754, in cancer samples from children with AML or myelodysplastic syndrome enrolled in the Children’s Oncology Group CCG-2961 trial comparing combination chemotherapy with or without bone marrow transplantation.

"Normally, in our work looking at changes in leukemia DNA, we ignore these polymorphisms, but we were surprised to find that patients that carry this SNP, which is present in about one-third of the American population, had a significantly improved overall survival," Dr. Ho said at a media briefing.

They found that the SNP was present in 25% of white patients, 21% of African Americans, 34% of Hispanics, and 53% of Asians in CCG-2961.

When they then looked at differences in toxicity-related deaths by ethnic group and SNP status, they found that the African American patients who were positive for rs16754 had no toxicity-related deaths, compared with 25% of African American patients who were SNP negative. Among patients of Asian background, the difference was even more pronounced, with none of the SNP-positive patients dying from treatment toxicity, compared with 43% of Asians who were SNP-negative.

Although the numbers of patients were small, there was evidence hinting that treatment-related mortality was higher among SNP-negative patients assigned to an experimental arm with a consolidation regimen containing the then-investigational agent fludarabine, Dr. Ho said.

He and his colleagues plan to validate the ethnicity-specific associations they found, and explore biologic mechanisms for the association of WT1 SNPs and patient outcomes, Dr. Ho said.

Heart failure markers

Dr. Bhatia presented data from a study led by Dr. Saro Armenian, a researcher in her laboratory. The investigators looked at polymorphisms that may contribute to anthracycline-related heart failure 1 or more years after a hematopoietic cell transplant (HCT).

They investigated candidate genes for anthracycline metabolism, iron homeostasis, antioxidant defense, and myocardial remodeling in a nested case-control study of all transplant patients at City of Hope from 1988 through 2008, including 77 HCT survivors with heart failure, and 178 without it.

They found that in addition to risk factors known to be associated with heart failure in transplant survivors such as female gender (odds ratio [OR], 3.0; P less than .01), radiation to the chest (OR, 5.6; P less than .05), and hypertension (OR, 3.5; P less than .05), three SNPs were significantly associated with risk. The suspect SNPs were in genes for the multidrug resistant protein (MRP2 –rs8187710; OR, 3.7; P less than .05), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit (RAC2 –rs13058338; OR, 3.0; P less than .01), and hemochromatosis (HFE2-rs1799945; OR, 2.4; P less than .05).

In multivariate analysis controlling for age at transplant, ethnicity, donor source, anthracycline dose, and follow-up time, the investigators saw that combinations of the risk factors increased the likelihood that survivors would develop heart failure. For example, females with two or more of the SNPs had a 17-fold greater risk (P less than .01), and males with two or more SNPs had a fivefold higher risk (P less than .05).

"There is biological plausibility to the genes that we have identified, and we are pretty certain this conglomeration of genes, along with the clinical factors, can predict a patient developing congestive heart failure," Dr. Bhatia said.

Dr. Ho’s and Dr. Bhatia’s studies were supported by the National Institutes of Health. Dr. Ho and Dr. Bhatia declared no relevant conflicts of interest.

ATLANTA – It doesn’t get more personal than this: genetic studies of individual patients can predict who is at increased risk for treatment-related toxicity or death, reported investigators at the annual meeting of the American Society of Hematology.

For example, a single nucleotide polymorphism (SNP) in the Wilms tumor gene (WT1) appears to predict lower risk for treatment-related mortality in children of African American and Asian ancestry with acute myeloid leukemia, reported Dr. Phoenix A. Ho from the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

Other recently identified polymorphisms appear to increase the risk of cardiotoxicity from exposure to anthracyclines in chemotherapy regimens, reported Dr. Smita Bhatia from the City of Hope Comprehensive Cancer Center in Duarte, Calif.

Protection from toxicity

Dr. Ho and his colleagues had previously identified mutations in the exon 7 region of WT1, a tumor suppressor and transcription factor gene that is over-expressed in an estimated 81% of AML cells compared with normal hematopoietic cells. Mutations in WT1 found in about 8% of children with AML are associated with worse prognosis, Dr. Ho said.

But during their investigation of mutations, the researchers also found apparently favorable single-nucleotide polymorphisms (SNPs), specifically a normal variant labeled rs16754, in cancer samples from children with AML or myelodysplastic syndrome enrolled in the Children’s Oncology Group CCG-2961 trial comparing combination chemotherapy with or without bone marrow transplantation.

"Normally, in our work looking at changes in leukemia DNA, we ignore these polymorphisms, but we were surprised to find that patients that carry this SNP, which is present in about one-third of the American population, had a significantly improved overall survival," Dr. Ho said at a media briefing.

They found that the SNP was present in 25% of white patients, 21% of African Americans, 34% of Hispanics, and 53% of Asians in CCG-2961.

When they then looked at differences in toxicity-related deaths by ethnic group and SNP status, they found that the African American patients who were positive for rs16754 had no toxicity-related deaths, compared with 25% of African American patients who were SNP negative. Among patients of Asian background, the difference was even more pronounced, with none of the SNP-positive patients dying from treatment toxicity, compared with 43% of Asians who were SNP-negative.

Although the numbers of patients were small, there was evidence hinting that treatment-related mortality was higher among SNP-negative patients assigned to an experimental arm with a consolidation regimen containing the then-investigational agent fludarabine, Dr. Ho said.

He and his colleagues plan to validate the ethnicity-specific associations they found, and explore biologic mechanisms for the association of WT1 SNPs and patient outcomes, Dr. Ho said.

Heart failure markers

Dr. Bhatia presented data from a study led by Dr. Saro Armenian, a researcher in her laboratory. The investigators looked at polymorphisms that may contribute to anthracycline-related heart failure 1 or more years after a hematopoietic cell transplant (HCT).

They investigated candidate genes for anthracycline metabolism, iron homeostasis, antioxidant defense, and myocardial remodeling in a nested case-control study of all transplant patients at City of Hope from 1988 through 2008, including 77 HCT survivors with heart failure, and 178 without it.

They found that in addition to risk factors known to be associated with heart failure in transplant survivors such as female gender (odds ratio [OR], 3.0; P less than .01), radiation to the chest (OR, 5.6; P less than .05), and hypertension (OR, 3.5; P less than .05), three SNPs were significantly associated with risk. The suspect SNPs were in genes for the multidrug resistant protein (MRP2 –rs8187710; OR, 3.7; P less than .05), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit (RAC2 –rs13058338; OR, 3.0; P less than .01), and hemochromatosis (HFE2-rs1799945; OR, 2.4; P less than .05).

In multivariate analysis controlling for age at transplant, ethnicity, donor source, anthracycline dose, and follow-up time, the investigators saw that combinations of the risk factors increased the likelihood that survivors would develop heart failure. For example, females with two or more of the SNPs had a 17-fold greater risk (P less than .01), and males with two or more SNPs had a fivefold higher risk (P less than .05).

"There is biological plausibility to the genes that we have identified, and we are pretty certain this conglomeration of genes, along with the clinical factors, can predict a patient developing congestive heart failure," Dr. Bhatia said.

Dr. Ho’s and Dr. Bhatia’s studies were supported by the National Institutes of Health. Dr. Ho and Dr. Bhatia declared no relevant conflicts of interest.

ATLANTA – It doesn’t get more personal than this: genetic studies of individual patients can predict who is at increased risk for treatment-related toxicity or death, reported investigators at the annual meeting of the American Society of Hematology.

For example, a single nucleotide polymorphism (SNP) in the Wilms tumor gene (WT1) appears to predict lower risk for treatment-related mortality in children of African American and Asian ancestry with acute myeloid leukemia, reported Dr. Phoenix A. Ho from the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

Other recently identified polymorphisms appear to increase the risk of cardiotoxicity from exposure to anthracyclines in chemotherapy regimens, reported Dr. Smita Bhatia from the City of Hope Comprehensive Cancer Center in Duarte, Calif.

Protection from toxicity

Dr. Ho and his colleagues had previously identified mutations in the exon 7 region of WT1, a tumor suppressor and transcription factor gene that is over-expressed in an estimated 81% of AML cells compared with normal hematopoietic cells. Mutations in WT1 found in about 8% of children with AML are associated with worse prognosis, Dr. Ho said.

But during their investigation of mutations, the researchers also found apparently favorable single-nucleotide polymorphisms (SNPs), specifically a normal variant labeled rs16754, in cancer samples from children with AML or myelodysplastic syndrome enrolled in the Children’s Oncology Group CCG-2961 trial comparing combination chemotherapy with or without bone marrow transplantation.

"Normally, in our work looking at changes in leukemia DNA, we ignore these polymorphisms, but we were surprised to find that patients that carry this SNP, which is present in about one-third of the American population, had a significantly improved overall survival," Dr. Ho said at a media briefing.

They found that the SNP was present in 25% of white patients, 21% of African Americans, 34% of Hispanics, and 53% of Asians in CCG-2961.

When they then looked at differences in toxicity-related deaths by ethnic group and SNP status, they found that the African American patients who were positive for rs16754 had no toxicity-related deaths, compared with 25% of African American patients who were SNP negative. Among patients of Asian background, the difference was even more pronounced, with none of the SNP-positive patients dying from treatment toxicity, compared with 43% of Asians who were SNP-negative.

Although the numbers of patients were small, there was evidence hinting that treatment-related mortality was higher among SNP-negative patients assigned to an experimental arm with a consolidation regimen containing the then-investigational agent fludarabine, Dr. Ho said.

He and his colleagues plan to validate the ethnicity-specific associations they found, and explore biologic mechanisms for the association of WT1 SNPs and patient outcomes, Dr. Ho said.

Heart failure markers

Dr. Bhatia presented data from a study led by Dr. Saro Armenian, a researcher in her laboratory. The investigators looked at polymorphisms that may contribute to anthracycline-related heart failure 1 or more years after a hematopoietic cell transplant (HCT).

They investigated candidate genes for anthracycline metabolism, iron homeostasis, antioxidant defense, and myocardial remodeling in a nested case-control study of all transplant patients at City of Hope from 1988 through 2008, including 77 HCT survivors with heart failure, and 178 without it.

They found that in addition to risk factors known to be associated with heart failure in transplant survivors such as female gender (odds ratio [OR], 3.0; P less than .01), radiation to the chest (OR, 5.6; P less than .05), and hypertension (OR, 3.5; P less than .05), three SNPs were significantly associated with risk. The suspect SNPs were in genes for the multidrug resistant protein (MRP2 –rs8187710; OR, 3.7; P less than .05), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit (RAC2 –rs13058338; OR, 3.0; P less than .01), and hemochromatosis (HFE2-rs1799945; OR, 2.4; P less than .05).

In multivariate analysis controlling for age at transplant, ethnicity, donor source, anthracycline dose, and follow-up time, the investigators saw that combinations of the risk factors increased the likelihood that survivors would develop heart failure. For example, females with two or more of the SNPs had a 17-fold greater risk (P less than .01), and males with two or more SNPs had a fivefold higher risk (P less than .05).

"There is biological plausibility to the genes that we have identified, and we are pretty certain this conglomeration of genes, along with the clinical factors, can predict a patient developing congestive heart failure," Dr. Bhatia said.

Dr. Ho’s and Dr. Bhatia’s studies were supported by the National Institutes of Health. Dr. Ho and Dr. Bhatia declared no relevant conflicts of interest.

ATLANTA – Patients with a positron-emission tomography–confirmed response to chemotherapy for Hodgkin’s lymphoma can be safely spared from radiotherapy without fear of compromising disease control, suggest results of studies presented at the annual meeting of the American Society of Hematology.

Among patients with Hodgkin’s lymphoma whose PET scans were negative for residual disease following three cycles of ABVD chemotherapy, the progression-free survival among patients who also received involved-field radiotherapy (IFRT) was 94.5% at a median of 48.6 months follow-up, compared with 90.8% of PET-negative patients who were not irradiated (intention-to-treat analysis), reported Dr. John Radford on behalf of the United Kingdom’s National Cancer Research Institute Lymphoma Clinical Studies Group.

"Using PET, it is possible to identify a population of patients with stages IA and IIA Hodgkin’s lymphoma who have an excellent outcome after three cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Crucially, however, these results have been obtained in the setting of, firstly, quality controlled PET image acquisition, secondly, central review of PET images at the core lab in London, and, thirdly, a comprehensive definition of ‘PET-negative,’ " said Dr. Radford.

He emphasized that longer follow-up is needed to determine what the effect of a PET-directed approach will be on 10- and 20-year survival and cause of death.

In a separate study, investigators led by Dr. Andrea Gallamini of San Croce General Hospital in Cuneo, Italy, found that the standard ABVD regimen is adequate therapy for PET-negative patients, and that the BEACOPP-escalated regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) was effective at rescuing PET-positive patients.

RAPID results

Dr. Radford reported results of the RAPID trial (Randomized Phase III Trial to Determine the Role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease).

The goal of the trial was to determine whether a negative PET scan is a good enough biomarker for response to therapy in patients with early-stage Hodgkin’s lymphoma to allow clinicians to safely omit IFRT.

They treated 602 adults with newly diagnosed Hodgkin’s lymphoma (139 of whom had stage IA disease and 281 with stage IIA disease) with three cycles of ABVD and then reassessed them for clinical response. Patients determined to have a response then underwent PET scans, and those who were PET positive went on to a fourth cycle of ABVD and IFRT. PET-negative patients were randomized to either IFRT at 30 Gy, or to no further treatment.

Of the 426 PET-negative patients, 420 were randomized – 209 to IFRT, and 211 to no additional therapy (3 patients chose not to be randomized, clinicians elected not to randomize 2, and 1 patient was not randomized due to an error).

Additionally, 25 PET-negative patients assigned to IFRT did not receive it, due to patient choice (19), deaths (5), or pneumonia (1).

In an intention-to-treat analysis, the hazard ratio for 3-year progression-free survival for PET-negative patients who also received IFRT was 1.51, but it was not statistically significant (P = .23)

In a per-protocol analysis of patients who received the allocated treatment (28 excluded for various reasons from the 420 randomized), the 3-year progression-free survival was 97% in the IFRT arm, and 90.7% in the no-further-treatment arm (HR in favor of IFRT 2.39, P equals .03). Dr. Radford noted, however, that in both the intention-to-treat and per-protocol analyses, the no-IFRT arm fell within the prespecified noninferiority margin.

Treatment intensification

Dr. Gallamini reported the first interim analysis of the GITIL/FIL (Gruppo Italiano Terapie Innovative Nei Linfomi/Fondazione Italiana Linfomi) HD0607 trial, in which patients with Hodgkin’s lymphoma who were PET positive after two cycles of ABVD were then randomized to escalated BEACOPP with or without rituximab. Patients who were PET negative continued on four additional cycles of ABVD.

Among 221 of 485 patients with at least 2-years of follow-up, the failure-free survival rate was 96.9% for patients who were PET negative after two cycles of ABVD compared with 82.7% for those who were PET negative (P less than .001)

"These results, although preliminary, show that a PET-adapted responsive treatment strategy is feasible in a multicenter prospective clinical trial, Dr. Gallamini said.

He added that the standard ABVD regimen appears to be sufficient for patients who are PET negative after two cycles.

The RAPID trial was supported by the UK National Health Service. Dr. Radford reported no relevant disclosures. The HD0607 trial is supported by the Italian Lymphoma Foundation. Dr. Gallamini reported serving on an advisory committee for Seattle Genetics Inc.

ATLANTA – Patients with a positron-emission tomography–confirmed response to chemotherapy for Hodgkin’s lymphoma can be safely spared from radiotherapy without fear of compromising disease control, suggest results of studies presented at the annual meeting of the American Society of Hematology.

Among patients with Hodgkin’s lymphoma whose PET scans were negative for residual disease following three cycles of ABVD chemotherapy, the progression-free survival among patients who also received involved-field radiotherapy (IFRT) was 94.5% at a median of 48.6 months follow-up, compared with 90.8% of PET-negative patients who were not irradiated (intention-to-treat analysis), reported Dr. John Radford on behalf of the United Kingdom’s National Cancer Research Institute Lymphoma Clinical Studies Group.

"Using PET, it is possible to identify a population of patients with stages IA and IIA Hodgkin’s lymphoma who have an excellent outcome after three cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Crucially, however, these results have been obtained in the setting of, firstly, quality controlled PET image acquisition, secondly, central review of PET images at the core lab in London, and, thirdly, a comprehensive definition of ‘PET-negative,’ " said Dr. Radford.

He emphasized that longer follow-up is needed to determine what the effect of a PET-directed approach will be on 10- and 20-year survival and cause of death.

In a separate study, investigators led by Dr. Andrea Gallamini of San Croce General Hospital in Cuneo, Italy, found that the standard ABVD regimen is adequate therapy for PET-negative patients, and that the BEACOPP-escalated regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) was effective at rescuing PET-positive patients.

RAPID results

Dr. Radford reported results of the RAPID trial (Randomized Phase III Trial to Determine the Role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease).

The goal of the trial was to determine whether a negative PET scan is a good enough biomarker for response to therapy in patients with early-stage Hodgkin’s lymphoma to allow clinicians to safely omit IFRT.

They treated 602 adults with newly diagnosed Hodgkin’s lymphoma (139 of whom had stage IA disease and 281 with stage IIA disease) with three cycles of ABVD and then reassessed them for clinical response. Patients determined to have a response then underwent PET scans, and those who were PET positive went on to a fourth cycle of ABVD and IFRT. PET-negative patients were randomized to either IFRT at 30 Gy, or to no further treatment.

Of the 426 PET-negative patients, 420 were randomized – 209 to IFRT, and 211 to no additional therapy (3 patients chose not to be randomized, clinicians elected not to randomize 2, and 1 patient was not randomized due to an error).

Additionally, 25 PET-negative patients assigned to IFRT did not receive it, due to patient choice (19), deaths (5), or pneumonia (1).

In an intention-to-treat analysis, the hazard ratio for 3-year progression-free survival for PET-negative patients who also received IFRT was 1.51, but it was not statistically significant (P = .23)

In a per-protocol analysis of patients who received the allocated treatment (28 excluded for various reasons from the 420 randomized), the 3-year progression-free survival was 97% in the IFRT arm, and 90.7% in the no-further-treatment arm (HR in favor of IFRT 2.39, P equals .03). Dr. Radford noted, however, that in both the intention-to-treat and per-protocol analyses, the no-IFRT arm fell within the prespecified noninferiority margin.

Treatment intensification

Dr. Gallamini reported the first interim analysis of the GITIL/FIL (Gruppo Italiano Terapie Innovative Nei Linfomi/Fondazione Italiana Linfomi) HD0607 trial, in which patients with Hodgkin’s lymphoma who were PET positive after two cycles of ABVD were then randomized to escalated BEACOPP with or without rituximab. Patients who were PET negative continued on four additional cycles of ABVD.

Among 221 of 485 patients with at least 2-years of follow-up, the failure-free survival rate was 96.9% for patients who were PET negative after two cycles of ABVD compared with 82.7% for those who were PET negative (P less than .001)

"These results, although preliminary, show that a PET-adapted responsive treatment strategy is feasible in a multicenter prospective clinical trial, Dr. Gallamini said.

He added that the standard ABVD regimen appears to be sufficient for patients who are PET negative after two cycles.

The RAPID trial was supported by the UK National Health Service. Dr. Radford reported no relevant disclosures. The HD0607 trial is supported by the Italian Lymphoma Foundation. Dr. Gallamini reported serving on an advisory committee for Seattle Genetics Inc.

ATLANTA – Patients with a positron-emission tomography–confirmed response to chemotherapy for Hodgkin’s lymphoma can be safely spared from radiotherapy without fear of compromising disease control, suggest results of studies presented at the annual meeting of the American Society of Hematology.

Among patients with Hodgkin’s lymphoma whose PET scans were negative for residual disease following three cycles of ABVD chemotherapy, the progression-free survival among patients who also received involved-field radiotherapy (IFRT) was 94.5% at a median of 48.6 months follow-up, compared with 90.8% of PET-negative patients who were not irradiated (intention-to-treat analysis), reported Dr. John Radford on behalf of the United Kingdom’s National Cancer Research Institute Lymphoma Clinical Studies Group.

"Using PET, it is possible to identify a population of patients with stages IA and IIA Hodgkin’s lymphoma who have an excellent outcome after three cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Crucially, however, these results have been obtained in the setting of, firstly, quality controlled PET image acquisition, secondly, central review of PET images at the core lab in London, and, thirdly, a comprehensive definition of ‘PET-negative,’ " said Dr. Radford.

He emphasized that longer follow-up is needed to determine what the effect of a PET-directed approach will be on 10- and 20-year survival and cause of death.

In a separate study, investigators led by Dr. Andrea Gallamini of San Croce General Hospital in Cuneo, Italy, found that the standard ABVD regimen is adequate therapy for PET-negative patients, and that the BEACOPP-escalated regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) was effective at rescuing PET-positive patients.

RAPID results

Dr. Radford reported results of the RAPID trial (Randomized Phase III Trial to Determine the Role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease).

The goal of the trial was to determine whether a negative PET scan is a good enough biomarker for response to therapy in patients with early-stage Hodgkin’s lymphoma to allow clinicians to safely omit IFRT.

They treated 602 adults with newly diagnosed Hodgkin’s lymphoma (139 of whom had stage IA disease and 281 with stage IIA disease) with three cycles of ABVD and then reassessed them for clinical response. Patients determined to have a response then underwent PET scans, and those who were PET positive went on to a fourth cycle of ABVD and IFRT. PET-negative patients were randomized to either IFRT at 30 Gy, or to no further treatment.

Of the 426 PET-negative patients, 420 were randomized – 209 to IFRT, and 211 to no additional therapy (3 patients chose not to be randomized, clinicians elected not to randomize 2, and 1 patient was not randomized due to an error).

Additionally, 25 PET-negative patients assigned to IFRT did not receive it, due to patient choice (19), deaths (5), or pneumonia (1).

In an intention-to-treat analysis, the hazard ratio for 3-year progression-free survival for PET-negative patients who also received IFRT was 1.51, but it was not statistically significant (P = .23)

In a per-protocol analysis of patients who received the allocated treatment (28 excluded for various reasons from the 420 randomized), the 3-year progression-free survival was 97% in the IFRT arm, and 90.7% in the no-further-treatment arm (HR in favor of IFRT 2.39, P equals .03). Dr. Radford noted, however, that in both the intention-to-treat and per-protocol analyses, the no-IFRT arm fell within the prespecified noninferiority margin.

Treatment intensification

Dr. Gallamini reported the first interim analysis of the GITIL/FIL (Gruppo Italiano Terapie Innovative Nei Linfomi/Fondazione Italiana Linfomi) HD0607 trial, in which patients with Hodgkin’s lymphoma who were PET positive after two cycles of ABVD were then randomized to escalated BEACOPP with or without rituximab. Patients who were PET negative continued on four additional cycles of ABVD.

Among 221 of 485 patients with at least 2-years of follow-up, the failure-free survival rate was 96.9% for patients who were PET negative after two cycles of ABVD compared with 82.7% for those who were PET negative (P less than .001)

"These results, although preliminary, show that a PET-adapted responsive treatment strategy is feasible in a multicenter prospective clinical trial, Dr. Gallamini said.

He added that the standard ABVD regimen appears to be sufficient for patients who are PET negative after two cycles.

The RAPID trial was supported by the UK National Health Service. Dr. Radford reported no relevant disclosures. The HD0607 trial is supported by the Italian Lymphoma Foundation. Dr. Gallamini reported serving on an advisory committee for Seattle Genetics Inc.

ATLANTA  – In young patients with high-risk diffuse large B-cell lymphoma, autologous stem cell transplantation can push the rate of progression-free survival beyond that achievable with rituximab and high-dose chemotherapy.

But transplants did not appear to confer an overall survival advantage for these patients in a study of 399 patients, Dr. Umberto Vitolo reported at the annual meeting of the American Society of Hematology.

More than a decade ago, rituximab transformed the treatment of diffuse large B-cell lymphoma (DLBCL), and called into question the role of intensified high-dose chemotherapy and transplantation as first-line therapy. But poorer outcomes for young patients with high-risk disease prompted Dr. Vitolo, of the University Hospital in Turin, Italy, and his colleagues to see whether treatment intensification after rituximab dose-dense chemotherapy, delivered at two different levels, could reduce risk in younger patients.

In a prospective phase III trial of the Italian Lymphoma Foundation, previously untreated adults aged 18-65 years (median age 49 years) with DLBCL and an age-adjusted IPI (International Prognostic Index) score of 2 or 3 were randomized to receive one of four regimens:

• Eight cycles of R-CHOP14 (rituximab-cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), prednisone).

• Six cycles of R-MegaCHOP14 (CHOP with a higher dose of cyclophosphamide).

• Four cycles of R-CHOP14 plus R-HDC (rituximab–high-dose chemotherapy) followed by BEAM (BCNU, etoposide, cytarabine, and melphalan) and ASTC (autologous stem-cell transplant).

• Four cycles of R-MegaCHOP14 plus R-HDC followed by BEAM and ASCT.

At a median of 41 months’ follow-up, 3-year progression-free survival was 75% among patients treated with the most intensive regimen of rituximab and high-dose chemotherapy followed by autologous stem-cell transplant. Three-year progression-free survival was 58% for the patients who got rituximab dose-dense chemotherapy (hazard ratio [HR], 0.63; P = .008).

There was no difference in overall survival, he said. Dose intensification in the chemotherapy-only arms did not offer additional benefit, and increased toxicities.

In all, 75% of 199 patients assigned to the two ASCT arms completed the trial, compared with 88% of 200 patients assigned to the two rituximab dose-dense only arms.

An intention-to-treat analysis showed that the combined complete response and complete response unconfirmed (CR/CRu) rates were 69% for the R-MegaCHOP14/ASCT arm, 82% for R-CHOP/ASCT, 73% for R-MegaCHOP14 only, and 71% for R-CHOP14 only. The respective partial response rates were 3%, 3%, 8%, and 13%, and nonresponse rates were 24%, 13%, 16%, and 15%.

A progression-free survival advantage was seen for the ASCT arms compared with the no-transplant arms. There was no significant difference in progression-free survival benefit in the chemotherapy only arms (65% for R-CHOP14, and 64% for R-MegaCHOP14; P = .73).

In an exploratory analysis comparing the four study arms with R-CHOP14 as the reference arm, R-CHOP14/ASCT only was associated with a significant reduction in risk of progression-free survival (HR, 0.56; confidence interval, 0.35-0.91).

Among intermediate to high-risk (age-adjusted IPI2) patients, 3-year progression-free survival was 75% for those treated with ASCT and 65% for those treated with chemotherapy only (HR, 0.63; P = .031). Among high-risk patients (IPI3), the respective rates were 60% and 46%, but the difference was not significant.

Among patients with any response (CR/CRu and PR) after four courses of chemotherapy, those who went on to transplant had a 3-year progression-free survival of 73%, compared with 62% for those who did not get a transplant (P = .018).

In multivariate analysis, the only significant prognostic factors were transplant, age at randomization, and bone marrow positive disease after treatment, said Dr. Vitolo.

Grade 3 or 4 hematologic toxicities were higher among patients in the transplant arms but were generally manageable, Dr. Vitolo said. The incidence of grade 3 febrile neutropenia was 2% among all transplant recipients, compared with 0.3% for nonrecipients; grade 4 events occurred in 0.2% vs. 0.08%, respectively. All patients had G-CSF (granulocyte colony-stimulating factor) support.

There were six treatment-related deaths (3%) among transplanted patients and four (2%) treatment-related deaths in the chemotherapy-only arms.

The study was supported by a grant from Compagnia SanPaolo/FIRMS, Turin. Dr. Vitolo disclosed serving in an advisory capacity to Roche, the marketer of rituximab.

ATLANTA  – In young patients with high-risk diffuse large B-cell lymphoma, autologous stem cell transplantation can push the rate of progression-free survival beyond that achievable with rituximab and high-dose chemotherapy.

But transplants did not appear to confer an overall survival advantage for these patients in a study of 399 patients, Dr. Umberto Vitolo reported at the annual meeting of the American Society of Hematology.

More than a decade ago, rituximab transformed the treatment of diffuse large B-cell lymphoma (DLBCL), and called into question the role of intensified high-dose chemotherapy and transplantation as first-line therapy. But poorer outcomes for young patients with high-risk disease prompted Dr. Vitolo, of the University Hospital in Turin, Italy, and his colleagues to see whether treatment intensification after rituximab dose-dense chemotherapy, delivered at two different levels, could reduce risk in younger patients.

In a prospective phase III trial of the Italian Lymphoma Foundation, previously untreated adults aged 18-65 years (median age 49 years) with DLBCL and an age-adjusted IPI (International Prognostic Index) score of 2 or 3 were randomized to receive one of four regimens:

• Eight cycles of R-CHOP14 (rituximab-cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), prednisone).

• Six cycles of R-MegaCHOP14 (CHOP with a higher dose of cyclophosphamide).

• Four cycles of R-CHOP14 plus R-HDC (rituximab–high-dose chemotherapy) followed by BEAM (BCNU, etoposide, cytarabine, and melphalan) and ASTC (autologous stem-cell transplant).

• Four cycles of R-MegaCHOP14 plus R-HDC followed by BEAM and ASCT.

At a median of 41 months’ follow-up, 3-year progression-free survival was 75% among patients treated with the most intensive regimen of rituximab and high-dose chemotherapy followed by autologous stem-cell transplant. Three-year progression-free survival was 58% for the patients who got rituximab dose-dense chemotherapy (hazard ratio [HR], 0.63; P = .008).

There was no difference in overall survival, he said. Dose intensification in the chemotherapy-only arms did not offer additional benefit, and increased toxicities.

In all, 75% of 199 patients assigned to the two ASCT arms completed the trial, compared with 88% of 200 patients assigned to the two rituximab dose-dense only arms.

An intention-to-treat analysis showed that the combined complete response and complete response unconfirmed (CR/CRu) rates were 69% for the R-MegaCHOP14/ASCT arm, 82% for R-CHOP/ASCT, 73% for R-MegaCHOP14 only, and 71% for R-CHOP14 only. The respective partial response rates were 3%, 3%, 8%, and 13%, and nonresponse rates were 24%, 13%, 16%, and 15%.

A progression-free survival advantage was seen for the ASCT arms compared with the no-transplant arms. There was no significant difference in progression-free survival benefit in the chemotherapy only arms (65% for R-CHOP14, and 64% for R-MegaCHOP14; P = .73).

In an exploratory analysis comparing the four study arms with R-CHOP14 as the reference arm, R-CHOP14/ASCT only was associated with a significant reduction in risk of progression-free survival (HR, 0.56; confidence interval, 0.35-0.91).

Among intermediate to high-risk (age-adjusted IPI2) patients, 3-year progression-free survival was 75% for those treated with ASCT and 65% for those treated with chemotherapy only (HR, 0.63; P = .031). Among high-risk patients (IPI3), the respective rates were 60% and 46%, but the difference was not significant.

Among patients with any response (CR/CRu and PR) after four courses of chemotherapy, those who went on to transplant had a 3-year progression-free survival of 73%, compared with 62% for those who did not get a transplant (P = .018).

In multivariate analysis, the only significant prognostic factors were transplant, age at randomization, and bone marrow positive disease after treatment, said Dr. Vitolo.

Grade 3 or 4 hematologic toxicities were higher among patients in the transplant arms but were generally manageable, Dr. Vitolo said. The incidence of grade 3 febrile neutropenia was 2% among all transplant recipients, compared with 0.3% for nonrecipients; grade 4 events occurred in 0.2% vs. 0.08%, respectively. All patients had G-CSF (granulocyte colony-stimulating factor) support.

There were six treatment-related deaths (3%) among transplanted patients and four (2%) treatment-related deaths in the chemotherapy-only arms.

The study was supported by a grant from Compagnia SanPaolo/FIRMS, Turin. Dr. Vitolo disclosed serving in an advisory capacity to Roche, the marketer of rituximab.

ATLANTA  – In young patients with high-risk diffuse large B-cell lymphoma, autologous stem cell transplantation can push the rate of progression-free survival beyond that achievable with rituximab and high-dose chemotherapy.

But transplants did not appear to confer an overall survival advantage for these patients in a study of 399 patients, Dr. Umberto Vitolo reported at the annual meeting of the American Society of Hematology.

More than a decade ago, rituximab transformed the treatment of diffuse large B-cell lymphoma (DLBCL), and called into question the role of intensified high-dose chemotherapy and transplantation as first-line therapy. But poorer outcomes for young patients with high-risk disease prompted Dr. Vitolo, of the University Hospital in Turin, Italy, and his colleagues to see whether treatment intensification after rituximab dose-dense chemotherapy, delivered at two different levels, could reduce risk in younger patients.

In a prospective phase III trial of the Italian Lymphoma Foundation, previously untreated adults aged 18-65 years (median age 49 years) with DLBCL and an age-adjusted IPI (International Prognostic Index) score of 2 or 3 were randomized to receive one of four regimens:

• Eight cycles of R-CHOP14 (rituximab-cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), prednisone).

• Six cycles of R-MegaCHOP14 (CHOP with a higher dose of cyclophosphamide).

• Four cycles of R-CHOP14 plus R-HDC (rituximab–high-dose chemotherapy) followed by BEAM (BCNU, etoposide, cytarabine, and melphalan) and ASTC (autologous stem-cell transplant).

• Four cycles of R-MegaCHOP14 plus R-HDC followed by BEAM and ASCT.

At a median of 41 months’ follow-up, 3-year progression-free survival was 75% among patients treated with the most intensive regimen of rituximab and high-dose chemotherapy followed by autologous stem-cell transplant. Three-year progression-free survival was 58% for the patients who got rituximab dose-dense chemotherapy (hazard ratio [HR], 0.63; P = .008).

There was no difference in overall survival, he said. Dose intensification in the chemotherapy-only arms did not offer additional benefit, and increased toxicities.

In all, 75% of 199 patients assigned to the two ASCT arms completed the trial, compared with 88% of 200 patients assigned to the two rituximab dose-dense only arms.

An intention-to-treat analysis showed that the combined complete response and complete response unconfirmed (CR/CRu) rates were 69% for the R-MegaCHOP14/ASCT arm, 82% for R-CHOP/ASCT, 73% for R-MegaCHOP14 only, and 71% for R-CHOP14 only. The respective partial response rates were 3%, 3%, 8%, and 13%, and nonresponse rates were 24%, 13%, 16%, and 15%.

A progression-free survival advantage was seen for the ASCT arms compared with the no-transplant arms. There was no significant difference in progression-free survival benefit in the chemotherapy only arms (65% for R-CHOP14, and 64% for R-MegaCHOP14; P = .73).

In an exploratory analysis comparing the four study arms with R-CHOP14 as the reference arm, R-CHOP14/ASCT only was associated with a significant reduction in risk of progression-free survival (HR, 0.56; confidence interval, 0.35-0.91).

Among intermediate to high-risk (age-adjusted IPI2) patients, 3-year progression-free survival was 75% for those treated with ASCT and 65% for those treated with chemotherapy only (HR, 0.63; P = .031). Among high-risk patients (IPI3), the respective rates were 60% and 46%, but the difference was not significant.

Among patients with any response (CR/CRu and PR) after four courses of chemotherapy, those who went on to transplant had a 3-year progression-free survival of 73%, compared with 62% for those who did not get a transplant (P = .018).

In multivariate analysis, the only significant prognostic factors were transplant, age at randomization, and bone marrow positive disease after treatment, said Dr. Vitolo.

Grade 3 or 4 hematologic toxicities were higher among patients in the transplant arms but were generally manageable, Dr. Vitolo said. The incidence of grade 3 febrile neutropenia was 2% among all transplant recipients, compared with 0.3% for nonrecipients; grade 4 events occurred in 0.2% vs. 0.08%, respectively. All patients had G-CSF (granulocyte colony-stimulating factor) support.

There were six treatment-related deaths (3%) among transplanted patients and four (2%) treatment-related deaths in the chemotherapy-only arms.

The study was supported by a grant from Compagnia SanPaolo/FIRMS, Turin. Dr. Vitolo disclosed serving in an advisory capacity to Roche, the marketer of rituximab.

ATLANTA – Lenalidomide, already an important agent in the treatment of multiple myeloma, is also flexing its muscles against non-Hodgkin’s lymphomas, reported researchers in two clinical trials presented at the annual meeting of the American Society for Hematology.

In a phase II study, lenalidomide (Revlimid) added to CHOP chemotherapy and rituximab (LR-CHOP21) produced a 92% overall response rate in elderly patients with untreated diffuse large B cell lymphoma (DLBCL), reported Dr. Annalisa Chiappella on behalf of the Italian Lymphoma Foundation in Alessandria, Italy.

"With a still limited follow-up, our data compare favorably with historical R-CHOP21 data, with a 2-year survival of 92% and a 2-year progression-free survival of 73%. LR-CHOP21 is able to induce a high 2-year progression-free survival of 65% also in poor-risk patients," Dr. Chiappella said.

In a separate study, single-agent lenalidomide also showed efficacy against relapsed/refractory mantle cell lymphoma (MCL), producing a 28% overall response rate for a median duration of 16.6 months, reported Dr. Andre Goy, chief of the lymphoma division at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center.

"This was a heavily pretreated population with a median of four prior therapies and a range of two to 10. Two-thirds were refractory to bortezomib [Velcade], more than half had a high tumor burden, one-third of the patients had bulky disease, and one-third had received prior transplants," Dr. Goy said.

CHOP add-on

In the Italian study, Dr. Chiappella and her colleagues looked at LR-CHOP21 in 49 patients (median age 69 years) with DLBCL. Nine of the patients had been treated with LR-CHOP21 at the maximum tolerated dose in phase I of the study.

The regimen consisted of six cycles of CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin [vincristine], and prednisone) plus rituximab at a dose of 375 mg/m², and lenalidomide at a dose of 15 mg daily on days 1-14 of each 21-day cycle.

Of the 294 total planned cycles of LR-CHOP21, 277 (94%) were administered. Some patients required a dose or a day reduction of lenalidomide, some received R-CHOP21 only, and some did not receive all planned cycles.

The final response, assessed after six cycles, included a complete response in 42 patients, a partial response in 3, no response in 3, and 1 death, for an overall response rate of 92%, At a median follow up of 22 months, the 2-year overall survival rate was 92%, which compares favorably with the 70% survival rate seen in historical controls treated with R-CHOP21 only, Dr. Chiappella said.

Of the four patient deaths, one was due to trauma, one to sepsis and multiple organ failure in a patient who had a complete response and had been off treatment for 6 months, one was due to heart failure, and one was from lymphoma progression.

The 2-year progression-free survival at 22 months’ median follow-up was 73%. The rate in R-CHOP21-treated historical controls was 57%.

Based on International Prognostic Index (IPI) risk, 2-year progression-free survival was 84% in patients with low- or intermediate-risk disease, and 65% in patients with intermediate/high-risk or high-risk disease.

Grade 3 or 4 adverse events in the per-protocol group included neutropenia (9% grade 3, 22% grade 4), febrile neutropenia (3%, 1%), leukocytopenia (15%, 13%), and thrombocytopenia (6%, 7%).

"These encouraging data warrant a future phase III randomized trial comparing LR-CHOP21 and R-CHOP21 in elderly patients with untreated DLBCL," Dr. Chiappella said.

MCL rescue

Dr. Goy and his colleagues looked at single-agent lenalidomide in patients with MCL who experienced disease relapse, progression, or who were refractory to bortezomib in the EMERGE trial (MCL-001 study).

In the phase II open-label study, 134 patients with MCL received lenalidomide 25 mg/day for 21 days out of every 28, with CT scans every two cycles until disease progression or unacceptable toxicities. The patients had to have failed prior anthracycline- or mitoxantrone-based therapy, cyclophosphamide, rituximab, and bortezomib.

The overall response rate by central review was 28%, with 8% of patients having a complete response or complete response unconfirmed (CR/CRu), 20% having a partial response, 29% having stable disease, and 26% experiencing disease progression.

The median time to response was 2.2 months, median time to CR/CRu was 3.7 months, median progression-free survival was 4 months, and median overall survival was 19 months at a median follow-up of 9.9 months. The median duration of response was more than 16 months, with the longest response more than 29 months at the time of data cutoff in July 2012.

The most common grade 3 or 4 adverse event was myelosuppression, consistent with the known safety profile of lenalidomide in non-Hodgkin’s lymphoma, Dr. Goy said.

Both Dr. Chiappella’s and Dr. Goy’s studies were supported in part by Celgene, maker of lenalidomide. Dr. Chiappella reported having no relevant disclosures. Dr. Goy is on Celgene’s speakers bureau.

ATLANTA – Lenalidomide, already an important agent in the treatment of multiple myeloma, is also flexing its muscles against non-Hodgkin’s lymphomas, reported researchers in two clinical trials presented at the annual meeting of the American Society for Hematology.

In a phase II study, lenalidomide (Revlimid) added to CHOP chemotherapy and rituximab (LR-CHOP21) produced a 92% overall response rate in elderly patients with untreated diffuse large B cell lymphoma (DLBCL), reported Dr. Annalisa Chiappella on behalf of the Italian Lymphoma Foundation in Alessandria, Italy.

"With a still limited follow-up, our data compare favorably with historical R-CHOP21 data, with a 2-year survival of 92% and a 2-year progression-free survival of 73%. LR-CHOP21 is able to induce a high 2-year progression-free survival of 65% also in poor-risk patients," Dr. Chiappella said.

In a separate study, single-agent lenalidomide also showed efficacy against relapsed/refractory mantle cell lymphoma (MCL), producing a 28% overall response rate for a median duration of 16.6 months, reported Dr. Andre Goy, chief of the lymphoma division at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center.

"This was a heavily pretreated population with a median of four prior therapies and a range of two to 10. Two-thirds were refractory to bortezomib [Velcade], more than half had a high tumor burden, one-third of the patients had bulky disease, and one-third had received prior transplants," Dr. Goy said.

CHOP add-on

In the Italian study, Dr. Chiappella and her colleagues looked at LR-CHOP21 in 49 patients (median age 69 years) with DLBCL. Nine of the patients had been treated with LR-CHOP21 at the maximum tolerated dose in phase I of the study.

The regimen consisted of six cycles of CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin [vincristine], and prednisone) plus rituximab at a dose of 375 mg/m², and lenalidomide at a dose of 15 mg daily on days 1-14 of each 21-day cycle.

Of the 294 total planned cycles of LR-CHOP21, 277 (94%) were administered. Some patients required a dose or a day reduction of lenalidomide, some received R-CHOP21 only, and some did not receive all planned cycles.

The final response, assessed after six cycles, included a complete response in 42 patients, a partial response in 3, no response in 3, and 1 death, for an overall response rate of 92%, At a median follow up of 22 months, the 2-year overall survival rate was 92%, which compares favorably with the 70% survival rate seen in historical controls treated with R-CHOP21 only, Dr. Chiappella said.

Of the four patient deaths, one was due to trauma, one to sepsis and multiple organ failure in a patient who had a complete response and had been off treatment for 6 months, one was due to heart failure, and one was from lymphoma progression.

The 2-year progression-free survival at 22 months’ median follow-up was 73%. The rate in R-CHOP21-treated historical controls was 57%.

Based on International Prognostic Index (IPI) risk, 2-year progression-free survival was 84% in patients with low- or intermediate-risk disease, and 65% in patients with intermediate/high-risk or high-risk disease.

Grade 3 or 4 adverse events in the per-protocol group included neutropenia (9% grade 3, 22% grade 4), febrile neutropenia (3%, 1%), leukocytopenia (15%, 13%), and thrombocytopenia (6%, 7%).

"These encouraging data warrant a future phase III randomized trial comparing LR-CHOP21 and R-CHOP21 in elderly patients with untreated DLBCL," Dr. Chiappella said.

MCL rescue

Dr. Goy and his colleagues looked at single-agent lenalidomide in patients with MCL who experienced disease relapse, progression, or who were refractory to bortezomib in the EMERGE trial (MCL-001 study).

In the phase II open-label study, 134 patients with MCL received lenalidomide 25 mg/day for 21 days out of every 28, with CT scans every two cycles until disease progression or unacceptable toxicities. The patients had to have failed prior anthracycline- or mitoxantrone-based therapy, cyclophosphamide, rituximab, and bortezomib.

The overall response rate by central review was 28%, with 8% of patients having a complete response or complete response unconfirmed (CR/CRu), 20% having a partial response, 29% having stable disease, and 26% experiencing disease progression.

The median time to response was 2.2 months, median time to CR/CRu was 3.7 months, median progression-free survival was 4 months, and median overall survival was 19 months at a median follow-up of 9.9 months. The median duration of response was more than 16 months, with the longest response more than 29 months at the time of data cutoff in July 2012.

The most common grade 3 or 4 adverse event was myelosuppression, consistent with the known safety profile of lenalidomide in non-Hodgkin’s lymphoma, Dr. Goy said.

Both Dr. Chiappella’s and Dr. Goy’s studies were supported in part by Celgene, maker of lenalidomide. Dr. Chiappella reported having no relevant disclosures. Dr. Goy is on Celgene’s speakers bureau.

ATLANTA – Lenalidomide, already an important agent in the treatment of multiple myeloma, is also flexing its muscles against non-Hodgkin’s lymphomas, reported researchers in two clinical trials presented at the annual meeting of the American Society for Hematology.

In a phase II study, lenalidomide (Revlimid) added to CHOP chemotherapy and rituximab (LR-CHOP21) produced a 92% overall response rate in elderly patients with untreated diffuse large B cell lymphoma (DLBCL), reported Dr. Annalisa Chiappella on behalf of the Italian Lymphoma Foundation in Alessandria, Italy.

"With a still limited follow-up, our data compare favorably with historical R-CHOP21 data, with a 2-year survival of 92% and a 2-year progression-free survival of 73%. LR-CHOP21 is able to induce a high 2-year progression-free survival of 65% also in poor-risk patients," Dr. Chiappella said.

In a separate study, single-agent lenalidomide also showed efficacy against relapsed/refractory mantle cell lymphoma (MCL), producing a 28% overall response rate for a median duration of 16.6 months, reported Dr. Andre Goy, chief of the lymphoma division at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center.

"This was a heavily pretreated population with a median of four prior therapies and a range of two to 10. Two-thirds were refractory to bortezomib [Velcade], more than half had a high tumor burden, one-third of the patients had bulky disease, and one-third had received prior transplants," Dr. Goy said.

CHOP add-on

In the Italian study, Dr. Chiappella and her colleagues looked at LR-CHOP21 in 49 patients (median age 69 years) with DLBCL. Nine of the patients had been treated with LR-CHOP21 at the maximum tolerated dose in phase I of the study.

The regimen consisted of six cycles of CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin [vincristine], and prednisone) plus rituximab at a dose of 375 mg/m², and lenalidomide at a dose of 15 mg daily on days 1-14 of each 21-day cycle.

Of the 294 total planned cycles of LR-CHOP21, 277 (94%) were administered. Some patients required a dose or a day reduction of lenalidomide, some received R-CHOP21 only, and some did not receive all planned cycles.

The final response, assessed after six cycles, included a complete response in 42 patients, a partial response in 3, no response in 3, and 1 death, for an overall response rate of 92%, At a median follow up of 22 months, the 2-year overall survival rate was 92%, which compares favorably with the 70% survival rate seen in historical controls treated with R-CHOP21 only, Dr. Chiappella said.

Of the four patient deaths, one was due to trauma, one to sepsis and multiple organ failure in a patient who had a complete response and had been off treatment for 6 months, one was due to heart failure, and one was from lymphoma progression.

The 2-year progression-free survival at 22 months’ median follow-up was 73%. The rate in R-CHOP21-treated historical controls was 57%.

Based on International Prognostic Index (IPI) risk, 2-year progression-free survival was 84% in patients with low- or intermediate-risk disease, and 65% in patients with intermediate/high-risk or high-risk disease.

Grade 3 or 4 adverse events in the per-protocol group included neutropenia (9% grade 3, 22% grade 4), febrile neutropenia (3%, 1%), leukocytopenia (15%, 13%), and thrombocytopenia (6%, 7%).

"These encouraging data warrant a future phase III randomized trial comparing LR-CHOP21 and R-CHOP21 in elderly patients with untreated DLBCL," Dr. Chiappella said.

MCL rescue

Dr. Goy and his colleagues looked at single-agent lenalidomide in patients with MCL who experienced disease relapse, progression, or who were refractory to bortezomib in the EMERGE trial (MCL-001 study).

In the phase II open-label study, 134 patients with MCL received lenalidomide 25 mg/day for 21 days out of every 28, with CT scans every two cycles until disease progression or unacceptable toxicities. The patients had to have failed prior anthracycline- or mitoxantrone-based therapy, cyclophosphamide, rituximab, and bortezomib.

The overall response rate by central review was 28%, with 8% of patients having a complete response or complete response unconfirmed (CR/CRu), 20% having a partial response, 29% having stable disease, and 26% experiencing disease progression.

The median time to response was 2.2 months, median time to CR/CRu was 3.7 months, median progression-free survival was 4 months, and median overall survival was 19 months at a median follow-up of 9.9 months. The median duration of response was more than 16 months, with the longest response more than 29 months at the time of data cutoff in July 2012.

The most common grade 3 or 4 adverse event was myelosuppression, consistent with the known safety profile of lenalidomide in non-Hodgkin’s lymphoma, Dr. Goy said.

Both Dr. Chiappella’s and Dr. Goy’s studies were supported in part by Celgene, maker of lenalidomide. Dr. Chiappella reported having no relevant disclosures. Dr. Goy is on Celgene’s speakers bureau.

ATLANTA – Responses to chimeric antigen receptor–modified T-cell therapy have been sustained beyond 2 years in a small cohort of patients with advanced chronic lymphocytic leukemia and no other curable options.

Three patients remain in complete remission at 7, 27, and 28 months, with no evidence of disease in their blood or bone marrow and complete resolution of all abnormal adenopathy.

Partial responses have been reported in four patients, including two with no evidence of CLL in their blood and bone marrow and more than a 50% reduction in bulky nodes at 2 and 3 months’ follow-up. The two other partial responders were treated earlier with an older vector lot that may not have been as potent, and had responses lasting approximately 4 months, Dr. David Porter said at the annual meeting of the American Society of Hematology.

Two of the nine evaluable patients had no response, for an overall response rate of 78%. Another patient was treated too recently to evaluate.

The findings represent a potential paradigm shift in the treatment of blood cancers, particularly for patients with advanced disease or with high-risk features. These patients are incurable except by allogeneic bone marrow or stem cell transplants, which are associated with extensive morbidity and mortality, he said.

In previous trials of chimeric antigen receptor (CAR) T cells, responses were modest and in vivo proliferation of the modified cells was not sustained. Investigators at the Hospital of the University of Pennsylvania, Philadelphia, then developed a second-generation CAR that targeted the B-cell antigen CD19, but was also linked to the CD3-zeta and CD137 (4-1BB) signaling domains. Preclinical observations showed that CD137 promotes the persistence of antigen-specific and antigen-nonspecific CAR T cells.

A pilot study reported a complete response within 3 weeks of treatment with the genetically modified T cells in a patient with advanced chronic lymphoid leukemia, who remains in remission today (N. Engl. J. Med. 2011;365:725-33). The therapy also resulted in the recovery of a 6-year-old with acute lymphoblastic leukemia as recently reported in the New York Times.

"So it’s now been in a definitive medical journal," quipped Dr. Porter.

On a more serious note, he acknowledged that in addition to its curative potential, "there is significant toxicity associated with this therapy." Five responders experienced grade 3-4 hepatotoxicity, with one patient on transient dialysis on several occasions for renal failure related to tumor lysis syndrome and hypotension.

Persistent B-cell aplasia with hypogammaglobulinemia developed in all patients achieving a complete remission, although treatment with intravenous immunoglobulin has been successful in preventing excessive or frequent infections.

In addition, all responding patients developed a rather profound cytokine release syndrome at the time of T-cell expansion, manifested by very high fevers, nausea, hypotension, and even capillary leak and hypoxia, said Dr. Porter, director of the blood and marrow transplantation program at the hospital.

Research revealed high levels of interleukin (IL)-6 (6-400x), interferon-gamma (89-1000), and IL-2R (5-25), but no significant increase in tumor necrosis factor–alpha or IL-2. Steroids reversed the syndrome in one patient. Given the cytokine profile, however, the switch was made to anticytokine therapy with tocilizumab (Actemra).

Cytokine release syndrome "can be treated effectively with anticytokine therapy, but what we don’t know is whether earlier treatment for the cytokine release syndrome is going to abrogate the T-cell activity and response," Dr. Porter said.

The 10 adult patients he reported had CD19-positive CLL that had been treated with at least two prior therapies (median 5; range 2-10) and progressed within 2 years of the last treatment. Three patients had the high-risk deletion 17p. Their median age was 66 years.

The patients received lympho-depleting chemotherapy 4-7 days before reinfusion with their genetically modified T cells using a lentivirus vector. The median cell dose was 7.5 x 10⁸ (range 1.7-50 x 10⁸), the infused dose of modified T cells was 1.4 x 10⁸ per kilogram, and the median follow-up was 8 months. There was no significant infusion-related toxicity, Dr. Porter said.

Responders experienced a massive expansion of T cells – 1,000- to 10,000-fold in vivo. This translated into a 2-log expansion in patients with a partial response and more than a 3-log expansion in complete responders. The expansion was associated with tumor lysis syndrome in complete responders.

The cells are at very high numbers early on after therapy, representing almost 15% of all the CD3-positive cells at 12 months and 1.2% at 18 months. The two long-term patients have levels of about 1% at 2 years, he said.

Deep whole transcriptome sequencing revealed no evidence of minimal residual disease in patients with a complete response.

The term "serial killer cells" has been coined because there has been an effector-to-target ratio of 1 in 1,000 to 1 in 93,000, meaning that the infused T cells, or their progeny, can kill up to 93,000 tumor cells, Dr. Porter said.

"When we do the math, we estimate that’s between 2.9 and 7.5 pounds of tumor in these patients that we’ve treated," he added.

During a discussion of the results, Dr. Porter said that in patients with cytokine release syndrome, anti-IL-6 therapy is typically given at the first sign of hemodynamic instability and that improvement is almost instantaneous. To address the B-cell dysplasia, he said, there is a lot of interest in developing either more specific targets or technology such as a suicide vector where the CARS are self-limited to allow for normal B-cell development.

In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to study and commercialize CAR therapies for other cancers at a Center for Advanced Cellular Therapies to be built on the university campus.

The research was supported in part by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy. Dr. Porter reported patents and royalties from Novartis, honoraria from Celgene, spouse employment with Genentech, and research funding from Pfizer. His coauthors reported commercial relationships with TxCell and Novartis.

[email protected]

ATLANTA – Responses to chimeric antigen receptor–modified T-cell therapy have been sustained beyond 2 years in a small cohort of patients with advanced chronic lymphocytic leukemia and no other curable options.

Three patients remain in complete remission at 7, 27, and 28 months, with no evidence of disease in their blood or bone marrow and complete resolution of all abnormal adenopathy.

Partial responses have been reported in four patients, including two with no evidence of CLL in their blood and bone marrow and more than a 50% reduction in bulky nodes at 2 and 3 months’ follow-up. The two other partial responders were treated earlier with an older vector lot that may not have been as potent, and had responses lasting approximately 4 months, Dr. David Porter said at the annual meeting of the American Society of Hematology.

Two of the nine evaluable patients had no response, for an overall response rate of 78%. Another patient was treated too recently to evaluate.

The findings represent a potential paradigm shift in the treatment of blood cancers, particularly for patients with advanced disease or with high-risk features. These patients are incurable except by allogeneic bone marrow or stem cell transplants, which are associated with extensive morbidity and mortality, he said.

In previous trials of chimeric antigen receptor (CAR) T cells, responses were modest and in vivo proliferation of the modified cells was not sustained. Investigators at the Hospital of the University of Pennsylvania, Philadelphia, then developed a second-generation CAR that targeted the B-cell antigen CD19, but was also linked to the CD3-zeta and CD137 (4-1BB) signaling domains. Preclinical observations showed that CD137 promotes the persistence of antigen-specific and antigen-nonspecific CAR T cells.

A pilot study reported a complete response within 3 weeks of treatment with the genetically modified T cells in a patient with advanced chronic lymphoid leukemia, who remains in remission today (N. Engl. J. Med. 2011;365:725-33). The therapy also resulted in the recovery of a 6-year-old with acute lymphoblastic leukemia as recently reported in the New York Times.

"So it’s now been in a definitive medical journal," quipped Dr. Porter.

On a more serious note, he acknowledged that in addition to its curative potential, "there is significant toxicity associated with this therapy." Five responders experienced grade 3-4 hepatotoxicity, with one patient on transient dialysis on several occasions for renal failure related to tumor lysis syndrome and hypotension.

Persistent B-cell aplasia with hypogammaglobulinemia developed in all patients achieving a complete remission, although treatment with intravenous immunoglobulin has been successful in preventing excessive or frequent infections.

In addition, all responding patients developed a rather profound cytokine release syndrome at the time of T-cell expansion, manifested by very high fevers, nausea, hypotension, and even capillary leak and hypoxia, said Dr. Porter, director of the blood and marrow transplantation program at the hospital.

Research revealed high levels of interleukin (IL)-6 (6-400x), interferon-gamma (89-1000), and IL-2R (5-25), but no significant increase in tumor necrosis factor–alpha or IL-2. Steroids reversed the syndrome in one patient. Given the cytokine profile, however, the switch was made to anticytokine therapy with tocilizumab (Actemra).

Cytokine release syndrome "can be treated effectively with anticytokine therapy, but what we don’t know is whether earlier treatment for the cytokine release syndrome is going to abrogate the T-cell activity and response," Dr. Porter said.

The 10 adult patients he reported had CD19-positive CLL that had been treated with at least two prior therapies (median 5; range 2-10) and progressed within 2 years of the last treatment. Three patients had the high-risk deletion 17p. Their median age was 66 years.

The patients received lympho-depleting chemotherapy 4-7 days before reinfusion with their genetically modified T cells using a lentivirus vector. The median cell dose was 7.5 x 10⁸ (range 1.7-50 x 10⁸), the infused dose of modified T cells was 1.4 x 10⁸ per kilogram, and the median follow-up was 8 months. There was no significant infusion-related toxicity, Dr. Porter said.

Responders experienced a massive expansion of T cells – 1,000- to 10,000-fold in vivo. This translated into a 2-log expansion in patients with a partial response and more than a 3-log expansion in complete responders. The expansion was associated with tumor lysis syndrome in complete responders.

The cells are at very high numbers early on after therapy, representing almost 15% of all the CD3-positive cells at 12 months and 1.2% at 18 months. The two long-term patients have levels of about 1% at 2 years, he said.

Deep whole transcriptome sequencing revealed no evidence of minimal residual disease in patients with a complete response.

The term "serial killer cells" has been coined because there has been an effector-to-target ratio of 1 in 1,000 to 1 in 93,000, meaning that the infused T cells, or their progeny, can kill up to 93,000 tumor cells, Dr. Porter said.

"When we do the math, we estimate that’s between 2.9 and 7.5 pounds of tumor in these patients that we’ve treated," he added.

During a discussion of the results, Dr. Porter said that in patients with cytokine release syndrome, anti-IL-6 therapy is typically given at the first sign of hemodynamic instability and that improvement is almost instantaneous. To address the B-cell dysplasia, he said, there is a lot of interest in developing either more specific targets or technology such as a suicide vector where the CARS are self-limited to allow for normal B-cell development.

In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to study and commercialize CAR therapies for other cancers at a Center for Advanced Cellular Therapies to be built on the university campus.

The research was supported in part by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy. Dr. Porter reported patents and royalties from Novartis, honoraria from Celgene, spouse employment with Genentech, and research funding from Pfizer. His coauthors reported commercial relationships with TxCell and Novartis.

[email protected]

ATLANTA – Responses to chimeric antigen receptor–modified T-cell therapy have been sustained beyond 2 years in a small cohort of patients with advanced chronic lymphocytic leukemia and no other curable options.

Three patients remain in complete remission at 7, 27, and 28 months, with no evidence of disease in their blood or bone marrow and complete resolution of all abnormal adenopathy.

Partial responses have been reported in four patients, including two with no evidence of CLL in their blood and bone marrow and more than a 50% reduction in bulky nodes at 2 and 3 months’ follow-up. The two other partial responders were treated earlier with an older vector lot that may not have been as potent, and had responses lasting approximately 4 months, Dr. David Porter said at the annual meeting of the American Society of Hematology.

Two of the nine evaluable patients had no response, for an overall response rate of 78%. Another patient was treated too recently to evaluate.

The findings represent a potential paradigm shift in the treatment of blood cancers, particularly for patients with advanced disease or with high-risk features. These patients are incurable except by allogeneic bone marrow or stem cell transplants, which are associated with extensive morbidity and mortality, he said.

In previous trials of chimeric antigen receptor (CAR) T cells, responses were modest and in vivo proliferation of the modified cells was not sustained. Investigators at the Hospital of the University of Pennsylvania, Philadelphia, then developed a second-generation CAR that targeted the B-cell antigen CD19, but was also linked to the CD3-zeta and CD137 (4-1BB) signaling domains. Preclinical observations showed that CD137 promotes the persistence of antigen-specific and antigen-nonspecific CAR T cells.

A pilot study reported a complete response within 3 weeks of treatment with the genetically modified T cells in a patient with advanced chronic lymphoid leukemia, who remains in remission today (N. Engl. J. Med. 2011;365:725-33). The therapy also resulted in the recovery of a 6-year-old with acute lymphoblastic leukemia as recently reported in the New York Times.

"So it’s now been in a definitive medical journal," quipped Dr. Porter.

On a more serious note, he acknowledged that in addition to its curative potential, "there is significant toxicity associated with this therapy." Five responders experienced grade 3-4 hepatotoxicity, with one patient on transient dialysis on several occasions for renal failure related to tumor lysis syndrome and hypotension.

Persistent B-cell aplasia with hypogammaglobulinemia developed in all patients achieving a complete remission, although treatment with intravenous immunoglobulin has been successful in preventing excessive or frequent infections.

In addition, all responding patients developed a rather profound cytokine release syndrome at the time of T-cell expansion, manifested by very high fevers, nausea, hypotension, and even capillary leak and hypoxia, said Dr. Porter, director of the blood and marrow transplantation program at the hospital.

Research revealed high levels of interleukin (IL)-6 (6-400x), interferon-gamma (89-1000), and IL-2R (5-25), but no significant increase in tumor necrosis factor–alpha or IL-2. Steroids reversed the syndrome in one patient. Given the cytokine profile, however, the switch was made to anticytokine therapy with tocilizumab (Actemra).

Cytokine release syndrome "can be treated effectively with anticytokine therapy, but what we don’t know is whether earlier treatment for the cytokine release syndrome is going to abrogate the T-cell activity and response," Dr. Porter said.

The 10 adult patients he reported had CD19-positive CLL that had been treated with at least two prior therapies (median 5; range 2-10) and progressed within 2 years of the last treatment. Three patients had the high-risk deletion 17p. Their median age was 66 years.

The patients received lympho-depleting chemotherapy 4-7 days before reinfusion with their genetically modified T cells using a lentivirus vector. The median cell dose was 7.5 x 10⁸ (range 1.7-50 x 10⁸), the infused dose of modified T cells was 1.4 x 10⁸ per kilogram, and the median follow-up was 8 months. There was no significant infusion-related toxicity, Dr. Porter said.

Responders experienced a massive expansion of T cells – 1,000- to 10,000-fold in vivo. This translated into a 2-log expansion in patients with a partial response and more than a 3-log expansion in complete responders. The expansion was associated with tumor lysis syndrome in complete responders.

The cells are at very high numbers early on after therapy, representing almost 15% of all the CD3-positive cells at 12 months and 1.2% at 18 months. The two long-term patients have levels of about 1% at 2 years, he said.

Deep whole transcriptome sequencing revealed no evidence of minimal residual disease in patients with a complete response.

The term "serial killer cells" has been coined because there has been an effector-to-target ratio of 1 in 1,000 to 1 in 93,000, meaning that the infused T cells, or their progeny, can kill up to 93,000 tumor cells, Dr. Porter said.

"When we do the math, we estimate that’s between 2.9 and 7.5 pounds of tumor in these patients that we’ve treated," he added.

During a discussion of the results, Dr. Porter said that in patients with cytokine release syndrome, anti-IL-6 therapy is typically given at the first sign of hemodynamic instability and that improvement is almost instantaneous. To address the B-cell dysplasia, he said, there is a lot of interest in developing either more specific targets or technology such as a suicide vector where the CARS are self-limited to allow for normal B-cell development.

In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to study and commercialize CAR therapies for other cancers at a Center for Advanced Cellular Therapies to be built on the university campus.

The research was supported in part by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy. Dr. Porter reported patents and royalties from Novartis, honoraria from Celgene, spouse employment with Genentech, and research funding from Pfizer. His coauthors reported commercial relationships with TxCell and Novartis.

[email protected]

Dr. David Henry, editor-in-chief of Community Oncology, shares some of his "did you know" picks from the annual meeting of the American Society of Hematology. His 5-minute report reviews the new international prognostic scoring system for myelodysplastic syndromes, gene expression profiling for diffuse large b-cell lymphoma, an approach to Waldenstrom’s macroglobulin anemia, gray zone lymphoma, multiple myeloma updates, and more.

Dr. David Henry, editor-in-chief of Community Oncology, shares some of his "did you know" picks from the annual meeting of the American Society of Hematology. His 5-minute report reviews the new international prognostic scoring system for myelodysplastic syndromes, gene expression profiling for diffuse large b-cell lymphoma, an approach to Waldenstrom’s macroglobulin anemia, gray zone lymphoma, multiple myeloma updates, and more.

Dr. David Henry, editor-in-chief of Community Oncology, shares some of his "did you know" picks from the annual meeting of the American Society of Hematology. His 5-minute report reviews the new international prognostic scoring system for myelodysplastic syndromes, gene expression profiling for diffuse large b-cell lymphoma, an approach to Waldenstrom’s macroglobulin anemia, gray zone lymphoma, multiple myeloma updates, and more.

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]

ATLANTA – The broad use of prophylactic platelet transfusions in adults with hematologic malignancies and severe thrombocytopenia will likely be narrowed in the wake of the randomized, international TOPPS trial.

The primary endpoint of grade 2 or higher bleeding, by World Health Organization criteria, was seen in 50% with no prophylaxis (151 of 300) and 43% receiving a prophylactic platelet transfusion (128 of 298). The adjusted difference in proportions was 8.4%, which fell below the 15.2% upper limit for confidence interval set for TOPPS (Trial of Prophylactic Platelet Transfusions).

Patrice Wendling/IMNG Medical Media

"This multicenter trial has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis," lead author Dr. Simon Stanworth said at the annual meeting of the American Society of Hematology.

A predefined subgroup analysis, however, found a significant difference in the primary endpoint between patients undergoing autologous stem cell transplantation (ASCT), who comprised 70% of the study population, and those receiving other treatments such as induction chemotherapy for acute myeloid leukemia (AML) or allogeneic bone marrow transplantation (P value = .04).

The rate of grade 2 or higher bleeding was very similar among patients undergoing autologous transplantation with or without prophylaxis (45% vs. 47%), while a clear benefit signal was seen in the subgroup of AML and allograft patients receiving treatment plus prophylaxis, compared with no prophylaxis (38% vs. 58%).

"Based on the results, the role of prophylactic platelet transfusions in different patient groups is varied and needs to be considered further," said Dr. Stanworth, a consultant hematologist with National Health Service Blood and Transplant, Oxford (England) University Hospital.

The finding that prophylactic platelets confer no advantage among those getting autologous transplants, however, could open up the opportunity to save millions of dollars in health care costs by skipping this unbeneficial treatment. An estimated 2 million platelets were transfused in the United States in 2008, a significant 16.7% increase from 2006, according to the latest National Blood Collection and Utilization Survey Report.

The results of TOPPS will likely change practice, but it will take time, Dr. Walter Dzik, codirector of the blood transfusion service at Massachusetts General Hospital, Boston, said in an interview.

"It takes quite some time, months to years, for knowledge transfer to occur and for well-established practices to change, but the end result will be to decrease the use of prophylactic platelets in autologous stem cell transplant patients," he said.

Prophylactic platelet transfusions are overused in the United States, in part because many clinicians transfuse their oncologic patients before they reach the recommended platelet prophylaxis threshold of 10 x 10⁹ platelets per liter (Transfusion 2007;47:201-5). Thousands of doses of platelets are also used each year outside of the context of hematology/oncology, in patients undergoing surgery or cardiac procedures, without evidenced-based indications.

During his formal introduction of the plenary abstract, Dr. Dzik said a study published 2 years ago begs the question of whether prophylactic platelets are needed at all, reporting that the number of platelets in a prophylactic transfusion had no effect on the incidence of hemorrhage in patients with hypoproliferative thrombocytopenia (N. Engl. J. Med. 2010;362:600-13).

He pointed out that a recent open-label German trial, however, agrees with the TOPPS data, also finding no advantage from prophylactic platelets in autologous transplants, and all of the advantage resting in allogeneic transplants and AML patients. There was an "unmistakable" reduction in WHO grade 2 bleeding overall, but there was no advantage with the prophylaxis in the amount of red blood cells used per patient, number of days in the hospital, or overall survival (Lancet 2012;380:1309-16). It is against this background that clinicians looked to the TOPPS trial for additional insights, Dr. Dzik observed.

TOPPS enrolled 600 patients with a hematologic malignancy who were receiving or expected to receive chemotherapy or stem cell transplant, and expected to be thrombocytopenic for at least 5 days. Patients were randomly assigned to receive prophylactic platelet transfusion if their platelet count fell below 10x10⁹/L, or no prophylaxis. Therapeutic platelets were given only after documented signs or symptoms of bleeding, prior to invasive procedures or at physician discretion.

Patients in the no-prophylaxis group were significantly less likely to receive a transfusion (59% vs. 89%), received fewer transfusions per patient (mean 1.7 vs. 3.0), and had more days with platelets less than 10,000/microL (mean 3.6 days vs. 1.8 days; all P less than .001, Dr. Stanworth reported.

Patients in the no-prophylaxis group averaged 1.7 days with a grade 2-4 bleed during follow-up vs. 1.2 days in the prophylaxis group (P value = .004), and developed an initial grade 2-4 bleed 2 days earlier than those receiving prophylaxis (hazard ratio 1.30; P = .02).

Still, there was no significant difference between the two groups in time to recovery from thrombocytopenia or a range of other outcomes including number of days in hospital or adverse events, Dr. Stanworth said.

Serious grade 3 or 4 bleeds occurred in one patient in the prophylaxis group (0.3%) and six in the no-prophylaxis group (2%). The difference did not reach statistical significance, but represents a sixfold increase in these sometimes life-threatening events (odds ratio 6.05; P = .13).

One intracranial bleed occurred in the no-prophylaxis group. Only two of the seven patients had a platelet count below 10x10⁹/L at the onset of grade 3-4 bleeding, and both were receiving induction chemotherapy for AML, he said.

During a discussion of the results, an audience member described the difference in bleeding between subgroups as remarkable, and suggested that AML patients should be taken far more seriously with regard to platelet prophylaxis because they may be especially predisposed to serious bleeding events because of endothelial damage during therapy. Dr. Stanworth concurred.

In his conclusion, Dr. Stanworth said there is clearly a need for new strategies to minimize the high burden of bleeding, and suggested that antifibrinolytics and the role of tranexamic acid should be explored.

For his part, Dr. Dzik said, "We need to stop approaching all patients as if they were the same and develop a risk score to identify those patients at higher risk of bleeding. The first question on the score will be ‘Are you an autologous stem cell case?’ and then tailor the degree of hemostatic support to match the risk of the patient."

TOPPS was funded by the National Health Service Blood and Transplant. Dr. Stanworth and Dr. Dzik reported no disclosures.

[email protected]

ATLANTA – The broad use of prophylactic platelet transfusions in adults with hematologic malignancies and severe thrombocytopenia will likely be narrowed in the wake of the randomized, international TOPPS trial.

The primary endpoint of grade 2 or higher bleeding, by World Health Organization criteria, was seen in 50% with no prophylaxis (151 of 300) and 43% receiving a prophylactic platelet transfusion (128 of 298). The adjusted difference in proportions was 8.4%, which fell below the 15.2% upper limit for confidence interval set for TOPPS (Trial of Prophylactic Platelet Transfusions).

Patrice Wendling/IMNG Medical Media

"This multicenter trial has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis," lead author Dr. Simon Stanworth said at the annual meeting of the American Society of Hematology.

A predefined subgroup analysis, however, found a significant difference in the primary endpoint between patients undergoing autologous stem cell transplantation (ASCT), who comprised 70% of the study population, and those receiving other treatments such as induction chemotherapy for acute myeloid leukemia (AML) or allogeneic bone marrow transplantation (P value = .04).

The rate of grade 2 or higher bleeding was very similar among patients undergoing autologous transplantation with or without prophylaxis (45% vs. 47%), while a clear benefit signal was seen in the subgroup of AML and allograft patients receiving treatment plus prophylaxis, compared with no prophylaxis (38% vs. 58%).

"Based on the results, the role of prophylactic platelet transfusions in different patient groups is varied and needs to be considered further," said Dr. Stanworth, a consultant hematologist with National Health Service Blood and Transplant, Oxford (England) University Hospital.

The finding that prophylactic platelets confer no advantage among those getting autologous transplants, however, could open up the opportunity to save millions of dollars in health care costs by skipping this unbeneficial treatment. An estimated 2 million platelets were transfused in the United States in 2008, a significant 16.7% increase from 2006, according to the latest National Blood Collection and Utilization Survey Report.

The results of TOPPS will likely change practice, but it will take time, Dr. Walter Dzik, codirector of the blood transfusion service at Massachusetts General Hospital, Boston, said in an interview.

"It takes quite some time, months to years, for knowledge transfer to occur and for well-established practices to change, but the end result will be to decrease the use of prophylactic platelets in autologous stem cell transplant patients," he said.

Prophylactic platelet transfusions are overused in the United States, in part because many clinicians transfuse their oncologic patients before they reach the recommended platelet prophylaxis threshold of 10 x 10⁹ platelets per liter (Transfusion 2007;47:201-5). Thousands of doses of platelets are also used each year outside of the context of hematology/oncology, in patients undergoing surgery or cardiac procedures, without evidenced-based indications.

During his formal introduction of the plenary abstract, Dr. Dzik said a study published 2 years ago begs the question of whether prophylactic platelets are needed at all, reporting that the number of platelets in a prophylactic transfusion had no effect on the incidence of hemorrhage in patients with hypoproliferative thrombocytopenia (N. Engl. J. Med. 2010;362:600-13).

He pointed out that a recent open-label German trial, however, agrees with the TOPPS data, also finding no advantage from prophylactic platelets in autologous transplants, and all of the advantage resting in allogeneic transplants and AML patients. There was an "unmistakable" reduction in WHO grade 2 bleeding overall, but there was no advantage with the prophylaxis in the amount of red blood cells used per patient, number of days in the hospital, or overall survival (Lancet 2012;380:1309-16). It is against this background that clinicians looked to the TOPPS trial for additional insights, Dr. Dzik observed.

TOPPS enrolled 600 patients with a hematologic malignancy who were receiving or expected to receive chemotherapy or stem cell transplant, and expected to be thrombocytopenic for at least 5 days. Patients were randomly assigned to receive prophylactic platelet transfusion if their platelet count fell below 10x10⁹/L, or no prophylaxis. Therapeutic platelets were given only after documented signs or symptoms of bleeding, prior to invasive procedures or at physician discretion.

Patients in the no-prophylaxis group were significantly less likely to receive a transfusion (59% vs. 89%), received fewer transfusions per patient (mean 1.7 vs. 3.0), and had more days with platelets less than 10,000/microL (mean 3.6 days vs. 1.8 days; all P less than .001, Dr. Stanworth reported.

Patients in the no-prophylaxis group averaged 1.7 days with a grade 2-4 bleed during follow-up vs. 1.2 days in the prophylaxis group (P value = .004), and developed an initial grade 2-4 bleed 2 days earlier than those receiving prophylaxis (hazard ratio 1.30; P = .02).

Still, there was no significant difference between the two groups in time to recovery from thrombocytopenia or a range of other outcomes including number of days in hospital or adverse events, Dr. Stanworth said.

Serious grade 3 or 4 bleeds occurred in one patient in the prophylaxis group (0.3%) and six in the no-prophylaxis group (2%). The difference did not reach statistical significance, but represents a sixfold increase in these sometimes life-threatening events (odds ratio 6.05; P = .13).

One intracranial bleed occurred in the no-prophylaxis group. Only two of the seven patients had a platelet count below 10x10⁹/L at the onset of grade 3-4 bleeding, and both were receiving induction chemotherapy for AML, he said.

During a discussion of the results, an audience member described the difference in bleeding between subgroups as remarkable, and suggested that AML patients should be taken far more seriously with regard to platelet prophylaxis because they may be especially predisposed to serious bleeding events because of endothelial damage during therapy. Dr. Stanworth concurred.

In his conclusion, Dr. Stanworth said there is clearly a need for new strategies to minimize the high burden of bleeding, and suggested that antifibrinolytics and the role of tranexamic acid should be explored.

For his part, Dr. Dzik said, "We need to stop approaching all patients as if they were the same and develop a risk score to identify those patients at higher risk of bleeding. The first question on the score will be ‘Are you an autologous stem cell case?’ and then tailor the degree of hemostatic support to match the risk of the patient."

TOPPS was funded by the National Health Service Blood and Transplant. Dr. Stanworth and Dr. Dzik reported no disclosures.

[email protected]

ATLANTA – The broad use of prophylactic platelet transfusions in adults with hematologic malignancies and severe thrombocytopenia will likely be narrowed in the wake of the randomized, international TOPPS trial.

The primary endpoint of grade 2 or higher bleeding, by World Health Organization criteria, was seen in 50% with no prophylaxis (151 of 300) and 43% receiving a prophylactic platelet transfusion (128 of 298). The adjusted difference in proportions was 8.4%, which fell below the 15.2% upper limit for confidence interval set for TOPPS (Trial of Prophylactic Platelet Transfusions).

Patrice Wendling/IMNG Medical Media

"This multicenter trial has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis," lead author Dr. Simon Stanworth said at the annual meeting of the American Society of Hematology.

A predefined subgroup analysis, however, found a significant difference in the primary endpoint between patients undergoing autologous stem cell transplantation (ASCT), who comprised 70% of the study population, and those receiving other treatments such as induction chemotherapy for acute myeloid leukemia (AML) or allogeneic bone marrow transplantation (P value = .04).

The rate of grade 2 or higher bleeding was very similar among patients undergoing autologous transplantation with or without prophylaxis (45% vs. 47%), while a clear benefit signal was seen in the subgroup of AML and allograft patients receiving treatment plus prophylaxis, compared with no prophylaxis (38% vs. 58%).

"Based on the results, the role of prophylactic platelet transfusions in different patient groups is varied and needs to be considered further," said Dr. Stanworth, a consultant hematologist with National Health Service Blood and Transplant, Oxford (England) University Hospital.

The finding that prophylactic platelets confer no advantage among those getting autologous transplants, however, could open up the opportunity to save millions of dollars in health care costs by skipping this unbeneficial treatment. An estimated 2 million platelets were transfused in the United States in 2008, a significant 16.7% increase from 2006, according to the latest National Blood Collection and Utilization Survey Report.

The results of TOPPS will likely change practice, but it will take time, Dr. Walter Dzik, codirector of the blood transfusion service at Massachusetts General Hospital, Boston, said in an interview.

"It takes quite some time, months to years, for knowledge transfer to occur and for well-established practices to change, but the end result will be to decrease the use of prophylactic platelets in autologous stem cell transplant patients," he said.

Prophylactic platelet transfusions are overused in the United States, in part because many clinicians transfuse their oncologic patients before they reach the recommended platelet prophylaxis threshold of 10 x 10⁹ platelets per liter (Transfusion 2007;47:201-5). Thousands of doses of platelets are also used each year outside of the context of hematology/oncology, in patients undergoing surgery or cardiac procedures, without evidenced-based indications.

During his formal introduction of the plenary abstract, Dr. Dzik said a study published 2 years ago begs the question of whether prophylactic platelets are needed at all, reporting that the number of platelets in a prophylactic transfusion had no effect on the incidence of hemorrhage in patients with hypoproliferative thrombocytopenia (N. Engl. J. Med. 2010;362:600-13).

He pointed out that a recent open-label German trial, however, agrees with the TOPPS data, also finding no advantage from prophylactic platelets in autologous transplants, and all of the advantage resting in allogeneic transplants and AML patients. There was an "unmistakable" reduction in WHO grade 2 bleeding overall, but there was no advantage with the prophylaxis in the amount of red blood cells used per patient, number of days in the hospital, or overall survival (Lancet 2012;380:1309-16). It is against this background that clinicians looked to the TOPPS trial for additional insights, Dr. Dzik observed.

TOPPS enrolled 600 patients with a hematologic malignancy who were receiving or expected to receive chemotherapy or stem cell transplant, and expected to be thrombocytopenic for at least 5 days. Patients were randomly assigned to receive prophylactic platelet transfusion if their platelet count fell below 10x10⁹/L, or no prophylaxis. Therapeutic platelets were given only after documented signs or symptoms of bleeding, prior to invasive procedures or at physician discretion.

Patients in the no-prophylaxis group were significantly less likely to receive a transfusion (59% vs. 89%), received fewer transfusions per patient (mean 1.7 vs. 3.0), and had more days with platelets less than 10,000/microL (mean 3.6 days vs. 1.8 days; all P less than .001, Dr. Stanworth reported.

Patients in the no-prophylaxis group averaged 1.7 days with a grade 2-4 bleed during follow-up vs. 1.2 days in the prophylaxis group (P value = .004), and developed an initial grade 2-4 bleed 2 days earlier than those receiving prophylaxis (hazard ratio 1.30; P = .02).

Still, there was no significant difference between the two groups in time to recovery from thrombocytopenia or a range of other outcomes including number of days in hospital or adverse events, Dr. Stanworth said.

Serious grade 3 or 4 bleeds occurred in one patient in the prophylaxis group (0.3%) and six in the no-prophylaxis group (2%). The difference did not reach statistical significance, but represents a sixfold increase in these sometimes life-threatening events (odds ratio 6.05; P = .13).

One intracranial bleed occurred in the no-prophylaxis group. Only two of the seven patients had a platelet count below 10x10⁹/L at the onset of grade 3-4 bleeding, and both were receiving induction chemotherapy for AML, he said.

During a discussion of the results, an audience member described the difference in bleeding between subgroups as remarkable, and suggested that AML patients should be taken far more seriously with regard to platelet prophylaxis because they may be especially predisposed to serious bleeding events because of endothelial damage during therapy. Dr. Stanworth concurred.

In his conclusion, Dr. Stanworth said there is clearly a need for new strategies to minimize the high burden of bleeding, and suggested that antifibrinolytics and the role of tranexamic acid should be explored.

For his part, Dr. Dzik said, "We need to stop approaching all patients as if they were the same and develop a risk score to identify those patients at higher risk of bleeding. The first question on the score will be ‘Are you an autologous stem cell case?’ and then tailor the degree of hemostatic support to match the risk of the patient."

TOPPS was funded by the National Health Service Blood and Transplant. Dr. Stanworth and Dr. Dzik reported no disclosures.

[email protected]

ATLANTA  – Patients with refractory multiple myeloma, including those with heavily pretreated disease, lived significantly longer with the immunomodulatory drug pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone alone in a phase III, head-to-head study.

Patients given pomalidomide (Pomalyst) and low-dose dexamethasone (Decadron) lived a median of 3.2 months without progression, compared with 1.7 months for patients on high-dose dexamethasone (hazard ratio, 0.45; P less than .001).

Moreover, the combination was equally beneficial in patients refractory to both lenalidomide (Revlimid) and bortezomib (Velcade) (3.2 vs. 1.7 months; HR, 0.48; P less than .001), who comprised three-fourths of the study cohort. Such patients are currently without standard treatment options and frequently receive only palliative care, Dr. Meletios Dimopoulos reported in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

An interim survival analysis also showed a statistically significant improvement in overall survival with the combination compared with high-dose dexamethasone (median not reached vs. 7.8 months; HR, 0.53; P less than .001), prompting the data-monitoring committee to recommend that patients in the control arm be allowed to cross over to pomalidomide plus low-dose dexamethasone.

"We believe that pomalidomide and low-dose dexamethasone should be considered as a new treatment option for these patients," said Dr. Dimopoulos of Alexandra Hospital, Athens.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York and comoderator of the session, described the MM-003 trial as a large, well-done "definitive" study.

"It’s a very active new agent, pomalidomide, a new IMiD, and I think it will emerge as a new standard of care for relapsed and refractory patients – a population for whom, as Dr. Dimopoulous indicated, we don’t have very good therapies" he said in an interview.

Pomalidomide, a derivative of thalidomide that acts as an immunomodulator, is expected to be approved in early 2013 in the United States, with a decision by European regulatory authorities in the second half of 2013, according to Celgene.

Dr. Dimopoulos said MM-003 did not address whether pomalidomide is more potent as a rescue therapy than carfilzomib (Kyprolis), a second-generation proteasome inhibitor granted accelerated approval in July 2012, for patients with multiple myeloma progressing after at least 2 prior therapies, including bortezomib and an IMiD. The approval was based on response rate only, with clinical benefit such as improved survival not yet verified.

"It is not possible to compare two different drugs from two different trials; however, as the myeloma community, we are encouraged that we now have carfilzomib and pomalidomide with low-dose dexamethasone that could be used to salvage, to rescue and help some patients with an unmet need in multiple myeloma," he said in an interview.

The MM-003 trial randomly assigned 455 patients with relapsed or refractory multiple myeloma to 4 mg oral pomalidomide on days 1-21 of a 28-day cycle plus oral dexamethasone 40 mg weekly, or to 40 mg high-dose dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle until disease progression. Patients older than 75 years in each arm received 20 mg dexamethasone on the same schedules.

All 302 patients in the experimental arm and 153 patients in the control arm had received prior lenalidomide and bortezomib, with 75% refractory to both. The median number of prior therapies was five in each arm, including dexamethasone, thalidomide, and stem cell transplant. One-third of all patients had renal impairment, defined by a creatinine clearance of less than 60 mL/min. The median age of patients in each arm was 64 and 65, respectively.

The overall response rate, defined as at least a partial response, was significantly higher in the experimental arm than the control arm at 21% vs. 3%, reaching 24% vs. 3% among patients randomized for at least 6 months (P less than .001), Dr. Dimopoulos reported.

Progression-free survival, the study’s primary endpoint, was significantly longer in patients on pomalidomide plus low-dose dexamethasone regardless of whether patients’ last prior treatment was bortezomib (median 3.6 vs. 1.8 months; HR, 0.47) or lenalidomide (median 3.7 vs. 1.8 months; HR, 0.38), or whether they had renal impairment (median 3.2 vs. 1.6 months; HR, 0.44; P less than .001 for all comparisons).

The combination therapy was generally well tolerated, although roughly one-third of patients experienced grade 3/4 neutropenia, an expected complication of pomalidomide (42% vs. 15% of controls), Dr. Dimopoulos observed.

Rates of any grade venous thromboembolism were low at 3% vs. 2% in controls, as were exacerbations of peripheral neuropathy at 12% vs. 11%. In all, 7% of patients discontinued pomalidomide plus low-dose dexamethasone, compared with 6% on high-dose dexamethasone, he said.

Session comoderator Dr. Agnes Lee of the University of British Columbia and Vancouver Coastal Health said her colleagues who enrolled patients in the trial are thrilled with having a possible new option for relapsed/refractory myeloma and very surprised with the minimal amount of toxicity they’ve seen. "Right now we’re just waiting for the next step – will this drug be available, especially here in Canada ... and whether it will now be investigated in earlier disease, especially when it’s so well tolerated."

Dr. Dimopoulos reported honoraria from the study sponsor, Celgene. Several of his coauthors reported commercial relationships with Celgene including employment and equity ownership. Dr. Tallman and Dr. Lee reported no relevant financial conflicts.

Dimopoulos, M.A. et al. Pomalidomide in combination with low-dose dexamethasone: Demonstrates a significant progression-free survival and overall survival advantage in relapsed/refractory MM: A phase 3, multicenter, randomized, open-label study. LBA-6.

[email protected]

ATLANTA  – Patients with refractory multiple myeloma, including those with heavily pretreated disease, lived significantly longer with the immunomodulatory drug pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone alone in a phase III, head-to-head study.

Patients given pomalidomide (Pomalyst) and low-dose dexamethasone (Decadron) lived a median of 3.2 months without progression, compared with 1.7 months for patients on high-dose dexamethasone (hazard ratio, 0.45; P less than .001).

Moreover, the combination was equally beneficial in patients refractory to both lenalidomide (Revlimid) and bortezomib (Velcade) (3.2 vs. 1.7 months; HR, 0.48; P less than .001), who comprised three-fourths of the study cohort. Such patients are currently without standard treatment options and frequently receive only palliative care, Dr. Meletios Dimopoulos reported in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

An interim survival analysis also showed a statistically significant improvement in overall survival with the combination compared with high-dose dexamethasone (median not reached vs. 7.8 months; HR, 0.53; P less than .001), prompting the data-monitoring committee to recommend that patients in the control arm be allowed to cross over to pomalidomide plus low-dose dexamethasone.

"We believe that pomalidomide and low-dose dexamethasone should be considered as a new treatment option for these patients," said Dr. Dimopoulos of Alexandra Hospital, Athens.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York and comoderator of the session, described the MM-003 trial as a large, well-done "definitive" study.

"It’s a very active new agent, pomalidomide, a new IMiD, and I think it will emerge as a new standard of care for relapsed and refractory patients – a population for whom, as Dr. Dimopoulous indicated, we don’t have very good therapies" he said in an interview.

Pomalidomide, a derivative of thalidomide that acts as an immunomodulator, is expected to be approved in early 2013 in the United States, with a decision by European regulatory authorities in the second half of 2013, according to Celgene.

Dr. Dimopoulos said MM-003 did not address whether pomalidomide is more potent as a rescue therapy than carfilzomib (Kyprolis), a second-generation proteasome inhibitor granted accelerated approval in July 2012, for patients with multiple myeloma progressing after at least 2 prior therapies, including bortezomib and an IMiD. The approval was based on response rate only, with clinical benefit such as improved survival not yet verified.

"It is not possible to compare two different drugs from two different trials; however, as the myeloma community, we are encouraged that we now have carfilzomib and pomalidomide with low-dose dexamethasone that could be used to salvage, to rescue and help some patients with an unmet need in multiple myeloma," he said in an interview.

The MM-003 trial randomly assigned 455 patients with relapsed or refractory multiple myeloma to 4 mg oral pomalidomide on days 1-21 of a 28-day cycle plus oral dexamethasone 40 mg weekly, or to 40 mg high-dose dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle until disease progression. Patients older than 75 years in each arm received 20 mg dexamethasone on the same schedules.

All 302 patients in the experimental arm and 153 patients in the control arm had received prior lenalidomide and bortezomib, with 75% refractory to both. The median number of prior therapies was five in each arm, including dexamethasone, thalidomide, and stem cell transplant. One-third of all patients had renal impairment, defined by a creatinine clearance of less than 60 mL/min. The median age of patients in each arm was 64 and 65, respectively.

The overall response rate, defined as at least a partial response, was significantly higher in the experimental arm than the control arm at 21% vs. 3%, reaching 24% vs. 3% among patients randomized for at least 6 months (P less than .001), Dr. Dimopoulos reported.

Progression-free survival, the study’s primary endpoint, was significantly longer in patients on pomalidomide plus low-dose dexamethasone regardless of whether patients’ last prior treatment was bortezomib (median 3.6 vs. 1.8 months; HR, 0.47) or lenalidomide (median 3.7 vs. 1.8 months; HR, 0.38), or whether they had renal impairment (median 3.2 vs. 1.6 months; HR, 0.44; P less than .001 for all comparisons).

The combination therapy was generally well tolerated, although roughly one-third of patients experienced grade 3/4 neutropenia, an expected complication of pomalidomide (42% vs. 15% of controls), Dr. Dimopoulos observed.

Rates of any grade venous thromboembolism were low at 3% vs. 2% in controls, as were exacerbations of peripheral neuropathy at 12% vs. 11%. In all, 7% of patients discontinued pomalidomide plus low-dose dexamethasone, compared with 6% on high-dose dexamethasone, he said.

Session comoderator Dr. Agnes Lee of the University of British Columbia and Vancouver Coastal Health said her colleagues who enrolled patients in the trial are thrilled with having a possible new option for relapsed/refractory myeloma and very surprised with the minimal amount of toxicity they’ve seen. "Right now we’re just waiting for the next step – will this drug be available, especially here in Canada ... and whether it will now be investigated in earlier disease, especially when it’s so well tolerated."

Dr. Dimopoulos reported honoraria from the study sponsor, Celgene. Several of his coauthors reported commercial relationships with Celgene including employment and equity ownership. Dr. Tallman and Dr. Lee reported no relevant financial conflicts.

Dimopoulos, M.A. et al. Pomalidomide in combination with low-dose dexamethasone: Demonstrates a significant progression-free survival and overall survival advantage in relapsed/refractory MM: A phase 3, multicenter, randomized, open-label study. LBA-6.

[email protected]

ATLANTA  – Patients with refractory multiple myeloma, including those with heavily pretreated disease, lived significantly longer with the immunomodulatory drug pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone alone in a phase III, head-to-head study.

Patients given pomalidomide (Pomalyst) and low-dose dexamethasone (Decadron) lived a median of 3.2 months without progression, compared with 1.7 months for patients on high-dose dexamethasone (hazard ratio, 0.45; P less than .001).

Moreover, the combination was equally beneficial in patients refractory to both lenalidomide (Revlimid) and bortezomib (Velcade) (3.2 vs. 1.7 months; HR, 0.48; P less than .001), who comprised three-fourths of the study cohort. Such patients are currently without standard treatment options and frequently receive only palliative care, Dr. Meletios Dimopoulos reported in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

An interim survival analysis also showed a statistically significant improvement in overall survival with the combination compared with high-dose dexamethasone (median not reached vs. 7.8 months; HR, 0.53; P less than .001), prompting the data-monitoring committee to recommend that patients in the control arm be allowed to cross over to pomalidomide plus low-dose dexamethasone.

"We believe that pomalidomide and low-dose dexamethasone should be considered as a new treatment option for these patients," said Dr. Dimopoulos of Alexandra Hospital, Athens.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York and comoderator of the session, described the MM-003 trial as a large, well-done "definitive" study.

"It’s a very active new agent, pomalidomide, a new IMiD, and I think it will emerge as a new standard of care for relapsed and refractory patients – a population for whom, as Dr. Dimopoulous indicated, we don’t have very good therapies" he said in an interview.

Pomalidomide, a derivative of thalidomide that acts as an immunomodulator, is expected to be approved in early 2013 in the United States, with a decision by European regulatory authorities in the second half of 2013, according to Celgene.

Dr. Dimopoulos said MM-003 did not address whether pomalidomide is more potent as a rescue therapy than carfilzomib (Kyprolis), a second-generation proteasome inhibitor granted accelerated approval in July 2012, for patients with multiple myeloma progressing after at least 2 prior therapies, including bortezomib and an IMiD. The approval was based on response rate only, with clinical benefit such as improved survival not yet verified.

"It is not possible to compare two different drugs from two different trials; however, as the myeloma community, we are encouraged that we now have carfilzomib and pomalidomide with low-dose dexamethasone that could be used to salvage, to rescue and help some patients with an unmet need in multiple myeloma," he said in an interview.

The MM-003 trial randomly assigned 455 patients with relapsed or refractory multiple myeloma to 4 mg oral pomalidomide on days 1-21 of a 28-day cycle plus oral dexamethasone 40 mg weekly, or to 40 mg high-dose dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle until disease progression. Patients older than 75 years in each arm received 20 mg dexamethasone on the same schedules.

All 302 patients in the experimental arm and 153 patients in the control arm had received prior lenalidomide and bortezomib, with 75% refractory to both. The median number of prior therapies was five in each arm, including dexamethasone, thalidomide, and stem cell transplant. One-third of all patients had renal impairment, defined by a creatinine clearance of less than 60 mL/min. The median age of patients in each arm was 64 and 65, respectively.

The overall response rate, defined as at least a partial response, was significantly higher in the experimental arm than the control arm at 21% vs. 3%, reaching 24% vs. 3% among patients randomized for at least 6 months (P less than .001), Dr. Dimopoulos reported.

Progression-free survival, the study’s primary endpoint, was significantly longer in patients on pomalidomide plus low-dose dexamethasone regardless of whether patients’ last prior treatment was bortezomib (median 3.6 vs. 1.8 months; HR, 0.47) or lenalidomide (median 3.7 vs. 1.8 months; HR, 0.38), or whether they had renal impairment (median 3.2 vs. 1.6 months; HR, 0.44; P less than .001 for all comparisons).

The combination therapy was generally well tolerated, although roughly one-third of patients experienced grade 3/4 neutropenia, an expected complication of pomalidomide (42% vs. 15% of controls), Dr. Dimopoulos observed.

Rates of any grade venous thromboembolism were low at 3% vs. 2% in controls, as were exacerbations of peripheral neuropathy at 12% vs. 11%. In all, 7% of patients discontinued pomalidomide plus low-dose dexamethasone, compared with 6% on high-dose dexamethasone, he said.

Session comoderator Dr. Agnes Lee of the University of British Columbia and Vancouver Coastal Health said her colleagues who enrolled patients in the trial are thrilled with having a possible new option for relapsed/refractory myeloma and very surprised with the minimal amount of toxicity they’ve seen. "Right now we’re just waiting for the next step – will this drug be available, especially here in Canada ... and whether it will now be investigated in earlier disease, especially when it’s so well tolerated."

Dr. Dimopoulos reported honoraria from the study sponsor, Celgene. Several of his coauthors reported commercial relationships with Celgene including employment and equity ownership. Dr. Tallman and Dr. Lee reported no relevant financial conflicts.

Dimopoulos, M.A. et al. Pomalidomide in combination with low-dose dexamethasone: Demonstrates a significant progression-free survival and overall survival advantage in relapsed/refractory MM: A phase 3, multicenter, randomized, open-label study. LBA-6.

[email protected]